tbuckley/cabot-search huggingface dataset:
IMMU-01. DEFINING THE IMMUNE PROFILE OF RADIATION NECROSIS THROUGH SINGLE-CELL ANALYSIS OF INTRACRANIAL LESIONS
Authors: Stephanie Robert, Benjamin Lu, Emre Kiziltug, Anna Estape, Don Nguyen, Veronica Chiang
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The incidence of radiation necrosis (RN), a common and morbid side effect of radiosurgical management of brain metastases, is growing as patient survival and use of immunotherapy increases. RN is thought to be immunologically driven; however, its pathophysiology remains poorly understood. Further, difficulty distinguishing it radiographically from recurrent metastatic disease often necessitates invasive brain biopsies for diagnosis. We sought to define the neuroimmune profile of RN to better understand the underlying pathophysiological mechanisms and improve patient diagnosis. METHODS Over 12 months, we collected intraoperative samples from patients undergoing craniotomy for RN and/or metastatic tumor. We created a bank of these 16 patient samples and processed them for scRNAseq analysis. Using fluorescence-activated cell sorting (FACS) and 10x Genomics single cell RNA sequencing, we analyzed the cellular immune profile of lesional tissue and time-matched blood from each patient. RESULTS Compared to metastases, RN demonstrates decreased expression of FOXP3, NKG7, and GZMB, markers of regulatory and cytotoxic T, and natural killer (NK) cells, and increased expression of interleukin-7 receptor (IL7R), a marker of naïve and memory T cells – profiles reflective of bystander transcriptional signatures. In contrast, metastatic tissue demonstrates an antigen-reactive profile, including commonly observed exhaustion signatures. Importantly, blood samples from patients also reflect these differences. Interestingly, increased IL7R is implicated in autoimmune disorders, suggesting an iatrogenically-induced autoreactive process underlying RN. DISCUSSION These findings demonstrate, firstly, the feasibility of extracting live cells from RN tissue, and, secondly, suggest RN and metastases have unique immune profiles that can be detected in patient blood. Therefore, in addition to beginning to define the immune landscape of this poorly understood pathology, this work has the potential to open new avenues for the development of improved diagnostic and therapeutic approaches to allow for earlier detection and more effective treatment of RN in metastatic brain tumors patients.
PATH-24. ACCURATE IDENTIFICATION OF GLIAL MALIGNANCIES FROM PERIPHERAL BLOOD
Authors: Giulio Anichini, Pooja Fulmali, Kevin O'Neill, Vineet Datta, Timothy Crook, Nelofer Syed
Journal: Neuro-Oncology (2022)

Abstract Symptomatic presentation of patients with intra-cranial malignancy is frequently non-specific and differentiating such patients from those with benign conditions is challenging. Accordingly, GBM presents as a medical emergency more frequently than any other common cancer, implying that effective strategies for rapid and simple diagnostic stratification of such patients are urgently required. Here we describe the detection of glial malignancies based on the enrichment and identification of Circulating Glial Cells (CGCs) in peripheral blood. The first case controlled study included blood from 189 participants split into discrete training and test sets (145 GBM, 44 benign CNS conditions). The second case controlled study included 40 cases of glial malignancies, 22 benign CNS conditions, 24 solid tumors with brain metastases, and 500 healthy individuals with no prior diagnosis of cancer and no current suspicion of cancer. A third prospective study was also carried out in 68 individuals with radiologically evident intracranial space-occupying lesion suspected of glial malignancies. Blood specimens were blindly evaluated for detection of CGCs through TruBlood assay to determine clinical sensitivity and specificity. 98% sensitivity and specificity was observed in detecting glial malignancies and differentiating them from benign CNS conditions in both case controlled studies. We detected and differentiated glial malignancies from benign CNS, healthy samples, and brain metastases. In the prospective study, 56 were positive for CGS, and 12 were negative for CGCs. All CGC positive specimens were confirmed glial malignancies and all CGC negative specimens benign CNS conditions. We present a non-invasive approach to the diagnostic stratification of patients presenting with suspicious but non-specific neurocognitive symptoms and hence early detection of glial malignancies. Moreover, immunocytochemistry facilitates the differentiation of GBM from metastatic intra-cranial epithelial cancers.
NCOG-40. UTILITY OF THE SEIZURE CONTROL COMPOSITE INDEX (RANO-SCCI) IN EVALUATING SEIZURES IN CNS TUMOR PATIENTS
Authors: Hope Miller, Alexa Christ, Ewa Grajkowska, Alvina Acquaye, Kendra Adegbesan, Lisa Boris, Eric Burton, Claudia Chambers, Anna Choi, Karen Evans, Amanda King, Edina Komlodi-Pasztor, Heather Leeper, Jason Levine, Matthew Lindsley, Nicole Lollo, Kelly Mentges, Marissa Panzer, Marta Penas-Prado, Valentina Pillai, Lily Polskin, Jennifer Reyes, Kayla Roche, James Rogers, Solmaz Sahebjam, Dilorom (Delia) Sass, Dorela Shuboni-Mulligan, Macy Stockdill, Brett Theeler, Kathleen Wall, Alex Wollet, Jing Wu, Jose Diarte, Mark Gilbert, Edward Avila, Terri Armstrong, Elizabeth Vera
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Seizures are a common symptom in patients with CNS tumors. The RANO-Seizure Control Composite Index (RANO-SCCI) was developed to monitor seizures over time by patients and clinicians. We describe the use of the RANO-SCCI as part of the NCI NOB-Natural History Study. METHODS Patients completed a RANO-SCCI prior to their clinic appointment with results shared with clinicians who then completed a RANO-SCCI as part of the same appointment. Seizure reports were tallied by respondent type and further by tumor type and grade. Concordance between patient and clinician report was also investigated. RESULTS One hundred fifty-seven patients underwent 250 clinical evaluations. Participants were primarily white (82%) males (57%) with median age 47 years (range: 19 – 78). Most had high grade (60%) primary brain (86%) tumors, were in surveillance (76%), with no prior recurrence (57%) and KPS ≥ 90 (76%). Half of patients and 62% of clinicians reported the patient ever having a seizure. The 12% discordance were all where the patient did not report a seizure, but clinicians did. There was good agreement on seizure reporting since last visit (74% patients, 78% clinicians), and anti-seizure medication use (51% patients, 57% clinicians). Seizures were reported more frequently in patients with high-grade tumors (WHO Grade 3 or 4) (60% patients, 76% clinicians) versus low-grade (WHO Grade 1 or 2) (51% patients, 59% clinicians), and among patients with oligodendrogliomas (71% patients, 85% clinicians) versus non-oligodendroglioma tumors (54% patients, 68% clinicians). CONCLUSIONS The RANO-SCCI was used for self-report and clinician report of seizure activity. A higher frequency was reported among oligodendroglioma and high-grade tumors. Disparities between patient and clinician responses may reveal a limitation in the patient’s ability to recognize and assess their seizure symptoms. Further work will investigate reporting congruence and associations with clinical and demographic characteristics.
EXTH-76. PRMT5 INHIBITION SENSITIZES GLIOBLASTOMA NEUROSPHERES TO TEMOZOLOMIDE
Authors: Sarah Rivas, Kimberly Rivera-Caraballo, Sara Murphy, Yoshihiro Otani, Allison Shelbourn, Leo Ampie, Dragan Maric, Stuart Walbridge, Ashish Shah, Yuanqing Yan, Ji young Yoo, John Heiss, Balveen Kaur, Yeshavanath Banasavadi-Siddegowda
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The median survival of Glioblastoma (GBM) patients is less than two years with the standard of care of maximal surgical resection, radiation, and temozolomide (TMZ) chemotherapy. Protein Arginine Methyltransferase 5 (PRMT5), which regulates cellular functions by symmetrically di-methylating arginine residues, is overexpressed in GBM. Inhibiting PRMT5 induces apoptosis in differentiated and senescence in stem-like GBM tumor cells. We inhibited PRMT5 in GBM neurospheres to determine if PRMT5 inhibition would enhance TMZ’s antitumor effect. METHODS We depleted PRMT5 activity, in vitro, using target-specific siRNA or LLY-283 and combined these with TMZ treatment. We evaluated the antitumor effect of this combination using cell viability assay, cell cycle analysis, apoptosis assay, and western blot. RESULTS TMZ reduced the viability of GBMNS with PRMT5 knockdown significantly more than the viability of PRMT5 intact GBMNS. The combination of TMZ and PRMT5 knockdown elevated the expression of cleaved caspase 3 and caspase3/7 indicating that PRMT5 knockdown enhanced the apoptotic effects of TMZ. Cell cycle analysis showed that depleting PRMT5 abrogated TMZ-induced G2/M cell cycle arrest. Further, treatment of PRMT5-depleted GBMNS with TMZ increased ɣ-H2AX expression compared PRMT5 intact GBMNS treated with TMZ, suggesting that PRMT5 depletion enhanced TMZ-induced DNA damage. PRMT5 knockdown also inhibited the symmetric di-methylation of RUVBL1 that is required for homologous recombination repair of TMZ treatment-related DNA damage. CONCLUSION Overall, PRMT5 inhibition sensitized GBMNS to TMZ and enhanced TMZ-related DNA damage and cytotoxicity. These findings support further development of this potential therapeutic combination.
CTIM-08. A PILOT STUDY OF ABEMACICLIB WITH BEVACIZUMAB IN RECURRENT GLIOBLASTOMA PATIENTS WITH LOSS OF CDKN2A/B OR GAIN OR AMPLIFICATION OF CDK4/6
Authors: Jennifer Murillo, Edward Pan, Michael Youssef, Omar Raslan, Elizabeth Maher, Robert Bachoo
Journal: Neuro-Oncology (2022)

Abstract The recurrence rate for glioblastomas is essentially 100% and median overall survival (OS) for recurrent glioblastoma patients is usually poor, approximately 6-8 months from first recurrence. There is an unmet need in recurrent glioblastomas for novel therapeutic options with favorable safety profiles and potentially longer OS. PURPOSE The goal was to assess the impact of treating recurrent Glioblastoma patients whose tumors harbor loss of CDKN2A and/or CDKN2B, and/or copy gains or amplifications of CDK4 and/or CDK6 with dual therapy Abemaciclib with Bevacizumab. METHODS This was a single institution, pilot study (N = 10) of recurrent glioblastoma patients given the combination of Abemaciclib with Bevacizumab. Study patients received the combination of Abemaciclib at 150 mg po bid daily along with intravenous Bevacizumab at 10 mg/kg once every 2 weeks within a 28-day cycle. Staging brain MRIs with contrast were obtained every 8 weeks. Trial patients were removed from the study for significant treatment toxicities, clinical or MRI progression, patient choice, or death. RESULTS A total of 10 patients were enrolled in the study. There were 3 patients initially enrolled that were evaluated for safety followed by the additional 7 patients meeting clinical accrual from Jan. 2020-Sept. 2021. A total of 9 patients received at least one cycle (M = 6, F = 3). Preliminary findings revealed a median PFS of 14 weeks (range 5 weeks–25 weeks) and median OS of 20 weeks (range 5-70 weeks). CONCLUSION The combination of Abemaciclib with Bevacizumab compared to monotherapy Bevacizumab, surprisingly, had poorer outcomes. In a 2014 Bevacizumab study in recurrent glioblastomas, the median PFS was 13 weeks and OS 34.8 weeks compared to our combination therapy study of 14 weeks and 20 weeks, respectively. It is postulated that the use of Bevacizumab with Abemaciclib caused a drug-drug interaction that led to poor outcomes in our pilot study.
SURG-09. EFFICACY OF A BIWEEKLY 3-STAGE STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: THE EFFECT OF EGFR TYROSINE-KINASE INHIBITOR ON TUMOR RESPONSE AND CLINICAL OUTCOMES
Authors: Ji-Eyon Kwon, Hyun Joo Park, So Young Ji, Jung Ho Han, Yong-Kil Hong, Chae-Yong Kim
Journal: Neuro-Oncology (2022)

Abstract Stereotactic radiosurgery(SRS) is one of primary treatment modalities for brain metastases(BM), however local control and radiation necrosis of large BM remain challenging. To overcome these limitations, biweekly 3-stage SRS for LBM was performed in this study. Total 53 patients were treated for 62 LBM. Female was 27(50.9%), and mean age was 63.7±11.8years. The mean KPS was 79.2±9.0 and GPA score was 1.9±0.7. Non-small cell lung cancer(NSCLC) was the most common primary cancer in 31 patients, others include 6 small cell lung cancer(SCLC), 9 gastro-intestinal tract cancer, 5 gynecological cancer, and etc. Epidermal growth factor receptor(EGFR) mutation was identified in 13 patients, and EGFR tyrosine-kinase inhibitor(TKI) was used in 10 patients during and after staged SRS. The mean tumor volume was 19.1cm3. The mean marginal dose of 11.7Gy was delivered to the 50% isodose line based on new treatment planning every two weeks. The mean tumor volume at the second and third stage was 14.8cm3 and 11.0cm3, respectively. The lesions from squamous cell carcinoma of NSCLC decreased most rapidly, and followed by gynecological cancer, SCLC and adenocarcinoma of NSCLC(volume ratio at 3rd stage was 0.39, 0.53, 0.56, and 0.64, respectively). The most significant factor related with tumor volume reduction at 3rd stage was usage of EGFR-TKI(p=0.016; LR analysis). The mean overall survival(OS) was 15.3months, and estimated OS were 62% and 46% at 6 and 12months. In the multivariate analysis, KPS(OR=0.918; 95% CI,0.871-0.968; p=0.002) and usage of EGFR-TKI(OR=0.216; 95% CI,0.059-0.790; p=0.021) were significantly associated with OS. The mean OS of the group of usage of EGFR-TKI was significantly longer than that of the others(20.7months, and 13.1months; p=0.029; log-rank test). The biweekly 3-stage SRS seems to be effective treatment for patients with LBM, especially in patients who were treated with EGFR-TKI during and/or after SRS, also cautiously considering the primary tumor origin.
NIMG-60. MAGNETIC RESONANCE SPECTROSCOPY IN THE DIAGNOSTIC AND MANAGEMENT OF PATIENTS WITH BRAIN TUMORS OF GLIAL ORIGIN
Authors: Pablo Moreno Acosta, Trinidad González Padín, Gina Malaver, Oscar Gamboa, Daniel Fino Villamil
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Magnetic resonance spectroscopy (MRS) is a quantitative technique based on the chemical shift of protons that allows the metabolic profile of tissues to be analyzed and characterized. Standard glial tumor analysis comprises Creatine (Cr), N-acetil aspartato (NAA) and Choline (Cho) metabolites, usually altered in brain pathologies (low grade tumor -LGT-, high-grade cancer -HGT-, metastasis -MTT-, gliosis -GLS-). The aim of this study is to analyze the feasibility of MRS technique in brain glial tumor diagnosis. METHODS The prospective study, approved by the Institutional Review Board, included 68 randomized patients (39 female and 29 male, mean age 47 y, with confirmed histopathology). Data was acquired at a Essenza Siemens 1.5T scanner, single voxel (SV) at the lesion (IT) and at healthy tissue (HT) in the contralateral hemisphere. A multivoxel (CS) sample was obtained from a ROI containing HT and IT. Postprocessing was done at Syngo workstation, statistical analyses were performed using SPSS v25.0 and p-values &amp;lt; 0.05 were considered statistically significant. RESULTS The group analysis (by pathology) for HT demonstrates homogeneity. For pathological ROIs (SV, long_TE), rNAA and rCho indexes (r stands for Cr ratio) had a p=0.003 and p=0.048 respectively; however, aCho (NAA ratio) had a p=0.11. For pathological regions, rNAA coefficient for LGT and GLS: p=0.008, LGT and MTT: p=0.02, HGT and MTT: p=0.008 and GLS with MTT: p=0.019. Meanwhile, for the rCho index, LGT and HGT: p=0.005, LGT and MTT: p=0.008, GLS and MTT: p=0.002. Short-TE SV demonstrates inhomogeneity between HT and only the aCho ratio allows to distinguish LGT and MTT (p=0.01) and GLS and MTT (p=0.008). Parametric map (from CS) of both rCho and aCho visually describes pathological regions (83% and 72%). CONCLUSIONS Long_TE-SV allows to characterize brain tumor lesions and CS provides a spatial metabolic description of the IT localization.
EXTH-74. ATR INHIBITION IN EXPERIMENTAL GLIOMA
Authors: Bianca Walter, Leonard Schnabel, Sophie Hirsch, Aaron Stahl, Lara Haeusser, Foteini Tsiami, Laurence Kuhlburger, Sven Nahnsen, Markus Templin, Katja Schenke-Layland, Daniel Merk, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma are incurable primary tumors of the central nervous system. Novel treatment options are urgently needed. Recently, we investigated molecular effects of disrupting the (b)HLH network, a frequently altered and tumor-promoting transcriptional network in glioma, by introducing a dominant-negative variant of the E47 protein. The identified downstream anti-tumor effects included the DNA damage response pathway. In the present study, we aimed at investigating the anti-glioma effects of ATR inhibition in vitro and in vivo with a particular focus on treatment-induced vulnerabilities and potential combination therapies. We performed acute cytotoxicity, clonogenic survival assays, flow cytometry-based determination of cell cycle status and apoptosis induction in human and murine glioma cell lines in vitro, and investigated tumor growth in the SMA560/VMDk syngeneic mouse model in vivo. Furthermore, we applied RNA sequencing, DigiWest protein profiling analyses and genome-wide CRISPR/Cas9 loss-of function and activation screens to determine potential combination therapies. Combination treatments were further analyzed for synergism by the Bliss and ZIP synergy models. ATR inhibition in glioma cells resulted in reduced viability and clonogenic survival. However, differential patterns of gene expression deregulation (e.g. p53 signaling) and differing modes of cell cycle arrest in distinct glioma model systems argue for a substantial heterogeneity with regard to response to ATR inhibition. Based on our data we designed combinatorial treatments. We will present novel insights into promising combinatorial treatments using ATR inhibition and their underlying molecular mechanisms.
EXTH-57. IDENTIFICATION OF NOVEL IMMUNE CHECKPOINT MOLECULE IN GLIOMA, LAIR1
Authors: Haipeng Tao, Dongjiang Chen, Changlin Yang, Linchun Jin, Christina Von Roemeling, Hector Mendez-Gomez, Ruixuan Liu, Duy Nguyen, Alicia Y Hou, Alfonso Pepe, Frances Weidert, Ashley Ghiaseddin, Duane Mitchell, Loic Deleyrolle, Elias Sayour, W Sawyer, David Tran, Jianping Huang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND In recent years, emerging evidence indicates that tumor-associated myeloid cells (TAMCs) affect cancer progression. But the molecular mechanisms and signaling pathways involved in the TAMCs’ interaction with extracellular matrix (ECM) and tumor stroma are incompletely understood. Checkpoint inhibition therapy targets immune inhibitory receptors, such as CTLA-4 and PD-1, which have become a major weapon in fighting cancer. These antibodies demonstrate apparent advantages such as being easy to use, broad applicability, and durable clinical response. Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), also called CD305, a collagen-binding immunoreceptor tyrosine-based inhibition motifs (ITIM)-bearing inhibitory receptor, was identified to present on almost all immune cell populations and overexpressed in cancers of human patients. However, LAIR1’s role and regulation in solid cancers are poorly defined. OBJECTIVE To identify LAIR1 as a new class of immune checkpoints in cancers that impacts TAMCs-associated tumor immunity. Further functional investigation warrants understanding the crosstalk between LAIR1-related immune checkpoint blocking agent(s), immune micro-environment, and its underlying mechanisms for targeted therapy development. METHODS Murine GBM cell line KR158-Luciferase cell line was used to set up the mouse model. Tumor-bearing mice were administered the Anti-LAIR1 blockade and IgG, followed by IVIS imaging for tumor growth and survival were recorded. The presentation and phenotype of immune cell populations in tumors and spleens were measured through scRNA-Seq. RESULTS GBM is one of these tumors that overexpress LAIR1 based on the TCGA analysis. LAIR1 molecules express highly on macrophages, monocytes, DCs, and activated T cells, not on the naive T cells. We found that LAIR1 blockade enhanced survival in preclinical GBM models. LAIR1 blockade reduced the presentation and function of TAMCs in tumors. What's more, LAIR1 blockade provided a synergetic antitumor effect with CD70 CAR T cells. CONCLUSION This study suggests that we identified a novel immune checkpoint molecule, LAIR1, which can limit tumor progression.
DISP-16. NUTRITIONAL SCREENING OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMOR SURVIVORS REVEALS HIGH PREVALENCE OF MALNOURISHMENT WITH SOCIODEMOGRAPHIC AND CLINICAL RISK FACTORS
Authors: Rebekah Wilson, Jacqueline Soja, Alexandra Yunker, Rahela Aziz-Bose, Erin Gordon, Christina Dieli-Conwright, Tab Cooney
Journal: Neuro-Oncology (2022)

Abstract Adult survivors of pediatric central nervous system (CNS) tumors are at the highest risk for morbidity and late mortality among all childhood cancers, partially due to chronic health conditions intersected with environmental and lifestyle factors. We aimed to study the prevalence of and risk factors for malnourishment (underweight, overweight, obese) amongst adult survivors of pediatric CNS tumors. We conducted a cross-sectional study assessing young adults (18-39 years) previously treated for pediatric CNS tumors who were followed in our survivorship clinic during 2016-2021. Sociodemographic, clinical, and treatment information was extracted from medical records with BMI status, per CDC guidelines, obtained from the most recent clinic visit. Data was assessed using one-way ANOVA, fishers exact test, and multivariable logistical regression. We identified 198 survivors (53% female, 84.3% white) categorized as underweight (4.0%), normal weight (40.9%), overweight (26.8%), obese (20.2%), and severely obese (8.1%). Patients were median age 8 years [4-12] at diagnosis and 24 years [20-28] at follow-up. Most common primary diagnosis and tumor location was low grade glioma (50.5%) and posterior fossa (39.4%) with 90.4% receiving surgery, 51.5% chemotherapy, and 52.5% radiotherapy. Male sex (OR 2.376, p = 0.006), hypothalamic/optic pathway tumor location (OR 2.362, P = 0.031), and radiation therapy (OR 2.844, p = 0.005) were associated with increased overweight/obesity risk, while chemotherapy (OR 0.363, p = 0.006) was associated with decreased risk. Male sex (OR 0.511, p = 0.007) and white ‘race’ (OR 0.166, p = 0.022) were associated with decreased underweight risk. The majority of young adult survivors seen in our clinic were not healthy weight by BMI, and the distribution of BMI groups appears comparable to contemporary studies of the general young adult U.S. population. The prevalence of malnourishment amongst PNO survivors warrants universal screening efforts with more accurate determinants of body composition than BMI, risk stratification, as well as targeted interventions.